Cyclodextrins (CD) are cyclic oligomers of glucose, which typically contain 6, 7, or 8 glucose monomers joined by α-1,4 linkages. These oligomers are commonly called α-CD, β-CD, and γ-CD, respectively. Higher oligomers containing up to 12 glucose monomers are known, but their preparation is more difficult.
Those skilled in the art of modifying cyclodextrins will understand that there are a number of ways to indicate the extent to which a cyclodextrin molecule has been modified. Each glucose unit of the cyclodextrin has three hydroxyls available at the 2, 3, and 6 positions. Hence, α-cyclodextrin has 18 hydroxyls or 18 substitution sites available and can have a maximum degree of substitution (DS) of 18. Similarly, β- and γ-cyclodextrin have a maximum DS of 21 and 24, respectively.
Often, DS is expressed as an average DS, defined as the number of substituents per glucose monomer. For example, β-CD having a maximum DS of 21 would have an average DS of 3 (21/7=3). As understood by those skilled in the art, the measured DS will relate to the analytical technique utilized. For example, DS by NMR will provide a single value. In contrast, a technique such as MALDI-TOF mass spectrometry will illustrate that these products are, in fact, a mixture of materials with varying degrees of substitution. Such distributions are Gaussian and the DS reported is generally the mean value.
Topologically, CD can be represented as a toroid in which the primary hydroxyls are located on the smaller circumference and the secondary hydroxyls are located on the larger circumference. Because of this arrangement, the interior of the torus is hydrophobic while the exterior is sufficiently hydrophilic to allow the CD to be dissolved in water. This difference between the interior and exterior faces allows the CD to act as a host molecule and to form inclusion complexes with guest molecules (otherwise called an “included material”), provided the guest molecule is of the proper size to fit in the cavity. The CD inclusion complex can then be dissolved in water, thereby providing for the introduction of a sparingly soluble guest molecule into an aqueous environment. This property makes CD inclusion complexes particularly useful in the pharmaceutical, cosmetic and food industries. Reviews of CD inclusion complexes can be found in Chem. Rev., 1997, 97, 1325–1357 and in Supramolecular Chemistry, 1995, 6, 217–223.
The production of CD involves first treating starch with an α-amylase to partially lower the molecular weight of the starch, followed by treatment with an enzyme known as cyclodextrin glucosyl transferase which forms the cyclic structure. By conducting the reaction in the presence of selected organic compounds, e.g., toluene, crystalline CD complexes can be formed which facilitate isolation of CD with a predetermined ring size. This process has been extensively reviewed by Szejtli et al., Compr. Supramol. Chem., 1996, 3, 41–56. This process yields the native CD discussed above. Table 1 provides a summary of selected physical properties of cyclodextrins.
TABLE 1Physical Properties of α-, β-, and γ-CD.Propertyα-CDβ-CDγ-CDNo. of Glucose Units678MW (anhydrous)97211351297Solubility (water, g/100 mL, 25° C.)14.51.923.2Optical Rotation αD (H2O)150.5162.0177.4Approximate Cavity Diameter (Angstroms)5.26.68.4
As seen in Table 1, there is an unexpected and marked drop in water solubility for β-CD relative to the α- and γ-CD. This is most unfortunate as β-CD has a highly desirable cavity size that is well suited for forming stable complexes with many pharmaceutically active agents. The β-CD is also the most abundant and lowest cost CD available.
Many investigators have found that the decreased water solubility of β-CD can be overcome somewhat by preparing derivatives with a low DS (typically lower than 7). A CD derivative with a low DS may be preferred for some uses because it has been shown in certain cases that the binding strength of the CD derivative with a pharmaceutical active decreases with increasing DS (Pitha, J., et al., Int. J. Pharmaceutics, 1988, 46, 217–222). It has also been shown that even a low level of substitution can substantially increase the water solubility relative to the parent β-CD. However, it should be noted that at a low DS level, some of the CD molecules would not contain a substituent. That is, there will be a distribution of cyclodextrin molecules in a reaction product, depending upon the target DS, in which some of the CD molecules will have no substituents, some will have 1 substituent, some will have 2 substituents, etc.
Substitution of β-CD is a highly desirable phenomenon for some uses. Specifically, unmodified β-CD has been shown to cause renal and liver damage after parenteral administration (Uekama, K., et al., Chem. Rev. 1998, 98, 2045–2076). Because of the lack of enzymes specific to β-CD in mammals, it is thought that the cyclodextrin molecules will remain intact after parenteral administration and hence accumulate in the renal tissue. Crystallization of the β-CD or its complexes leads to the observed necrotic damage. Hence, the use of unmodified CD in a clinical setting is generally limited to oral or topical pharmaceutical formulations.
Many neutral and charged CD derivatives are known. The neutral CD derivatives are typically ethers prepared by displacement of halides (U.S. Pat. No. 4,638,058) or by opening of epoxides (U.S. Pat. No. 4,727,064). In special cases, the ether may be polyhydroxylated (European Pat. Publication No. 486445 A2). Methods of ether formation via epoxide opening are disclosed in U.S. Pat. Nos. 3,459,731 and 4,727,064. The preferred epoxides are ethylene oxide (EO) and propylene oxide (PO).
A recent invention by Buchanan et al., U.S. Provisional App. No. 60/203,500, the disclosure of which is incorporated herein in its entirety by this reference, discloses hydroxybutenyl cyclodextrin (HBenCD™) or mixed ethers of HBenCD™ (HBenRCD) as new neutral CD derivatives, processes for the preparation of these new derivatives, and uses for the new CD derivatives (HBenCD is a registered trade name of Eastman Chemical Company).
There are many reports in the prior art related to charged CD derivatives. These charged CD derivatives may be anionic, cationic, or zwitterionic. For example, Parmeter et al. (U.S. Pat. No. 3,426,011 the disclosure of which is herein incorporated by this reference in its entirety) disclose the preparation of anionic cyclodextrins in which the charged group may be any organic acid group such as phosphoric acid, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, or carboxylic acid. Further examples of the preparation of anionic CD derivatives can be found in U.S. Pat. Nos. 5,134,127 and 5,376,645, the disclosure of which is herein incorporated in its entirety by this reference.
The preparation of cyclodextrin allyl ethers and their subsequent conversion to charged cyclodextrin derivatives has been disclosed. For example, Wenz and Hofler (Carbohydr. Res. 1999, 322, 153–165) have described the preparation of regioselectively and statistically substituted allyl and 3-allyloxy-2-hydroxypropyl cyclodextrin ethers. In a second example of the preparation of cyclodextrin allyl ethers and their subsequent conversion to charged cyclodextrin derivatives, Leydet et al. have described the preparation of perallylated cyclodextrins and their conversion in two steps to anionic and zwitterionic cyclodextrin derivatives.